rs45604036

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020937.4(FANCM):c.3758A>G(p.Asn1253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,604,822 control chromosomes in the GnomAD database, including 812 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 64 hom., cov: 32)

Exomes 𝑓: 0.030 ( 748 hom. )

Consequence

FANCM
NM_020937.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.196

Variant links:

Genes affected

FANCM (HGNC:23168): (FA complementation group M) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

FANCM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032918155).

BP6

Variant 14-45176512-A-G is Benign according to our data. Variant chr14-45176512-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45176512-A-G is described in Lovd as [Benign]. Variant chr14-45176512-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.022 (3356/152332) while in subpopulation SAS AF= 0.0351 (169/4820). AF 95% confidence interval is 0.0308. There are 64 homozygotes in gnomad4. There are 1655 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.3758A>G	p.Asn1253Ser	missense_variant	Exon 14 of 23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.3758A>G	p.Asn1253Ser	missense_variant	Exon 14 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3355

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00463

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.00962

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0319

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0250

AC:

6083

AN:

243484

Hom.:

AF XY:

0.0262

AC XY:

3452

AN XY:

131552

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.0361

Gnomad FIN exome

AF:

0.0479

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0295

AC:

42901

AN:

1452490

Hom.:

748

Cov.:

AF XY:

0.0299

AC XY:

21589

AN XY:

721800

show subpopulations

Gnomad4 AFR exome

AF:

0.00491

Gnomad4 AMR exome

AF:

0.00734

Gnomad4 ASJ exome

AF:

0.0172

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0360

Gnomad4 FIN exome

AF:

0.0487

Gnomad4 NFE exome

AF:

0.0315

Gnomad4 OTH exome

AF:

0.0238

GnomAD4 genome

AF:

0.0220

AC:

3356

AN:

152332

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1655

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00462

Gnomad4 AMR

AF:

0.00960

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0351

Gnomad4 FIN

AF:

0.0499

Gnomad4 NFE

AF:

0.0319

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0288

Hom.:

117

Bravo

AF:

0.0173

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0251

AC:

3048

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Premature ovarian failure 15

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.058

DANN

Benign

0.29

DEOGEN2

Benign

0.052

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.63

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.029

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.76

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.097

MPC

0.069

ClinPred

0.0026

GERP RS

-3.9

Varity_R

0.022

gMVP

0.096

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over